Neurological Manifestations of Mitochondrial Disease

Neurological Manifestations of Mitochondrial Disease

Neurological Manifestations
of Mitochondrial Disease
Russell P. Saneto, DO, PhD
Children’s Hospital & Regional Medical
Center/University of Washington
Disclaimer
„
„
„
I will be discussing off-label use for many
different medications.
Information is based on personal experience
and case reports or small studies published
in the literature.
Disclosures:
‰
‰
I am a lecturer for GlaxoSmithKline.
I have served as a consultant for Abbott Labs and
Ortho-McNeil.
My Background
„
Clinically, I am a Pediatrician, Neurologist,
and Epileptologist (DO and Fellowship).
‰
‰
„
Medical School: Des Moines University.
Residency and Fellowship: Cleveland Clinic.
My early education was in human genetics
and neurobiology (PhD and Fellowship).
‰
‰
‰
PhD: NIH Pre-Doctoral at University of Texas.
NIH Post-Fellowship: UCLA.
Jeanne Kempner Fellow: UCLA
My Background
„
My approach based on:
‰
‰
‰
Wisdom from my teachers and mentors.
Experience acquired along the way.
Knowledge gleaned by my patients and their
parents have been my major teacher.
Specific Aims
„
Introduction
‰
‰
‰
„
Bioenergetic dysfunction in the central nervous system.
Brain function and energy
Nerve function
Primary CNS Manifestations
‰
‰
Learning disorders
Motor functions
„
„
„
Gross motor
Fine motor
Coordination
Specific Aims
‰
Epilepsy
„
„
„
„
‰
‰
‰
‰
‰
‰
Syndromes
EEG
Treatments
Epilepsy mimics
Movement disorders
Sleep Disorders
Autonomic Failure and Gastrointestinal Dysmotility.
Headache
Stroke and Stroke-Like Events.
Psychiatric
„
Anxiety, depression, psychosis, hallucinations,
coma, and behavior problems.
Introduction
„
The Brain
‰
‰
‰
‰
2% of body weight
20% of body oxygen consumption
Approximately 60% to 70% of body energy.
Dependent on oxidative phosphorylation.
Introduction
„
Mitochondria are intracellular organelles responsible
for energy production.
‰
‰
„
Brain is composed of neurons and glial cells.
‰
„
Found in all cell types with the exception of mature red
blood cells.
Up to 100s of mitochondria per cell.
„ Those cells requiring more energy to function have the
most mitochondria; neurons and muscle cells.
Neurons mainly use glucose for energy.
Therefore, the brain has a high energy demand and
is particularly sensitive to abnormal energy
production.
Introduction
„
Neurons prefer glucose for their function.
‰
‰
‰
ATP needed to generate electrical signaling, i.e. nerve
action potential.
Electrical signal is transferred to chemical signals at the
synapse (end of the axon) to either other neurons (in the
brain) or neurons and muscle cells outside the brain (in the
peripheral nervous system and musculoskeletal system).
Electrical energy is made (transferred) into chemical
signaling, Chemical signaling imparts specificity of one
signal (neurotransmitter) to only the neurons that have a
specific receptor for that neurotransmitter. This specificity
allows selective communication between neurons and brain
areas.
Introduction
Introduction
„
Development
‰
During development more neurons send their axons to
specific areas of function than are needed.
„
‰
Sprouting or sending out axons requires a lot of energy.
As the specific function becomes more “hard wired” or
entrained, the brain “prunes” away those axons (neurons)
that are not needed.
„
Those “neurons that fire together stay together”, others are
pruned away. This is what we mean by developing eloquence.
‰
Pathways become “hard-wired” as excess neurons are pruned
away and neurons becomes specialized for particular functions.
Introduction
Introduction
„
Different parts of the brain have different energy
needs.
‰
‰
Vary during development.
Functions vary depending on need (examples):
„
„
„
„
Cognition
Executive function
Vision
Motor function
‰
„
Fine motor > Gross motor
Autonomic function
‰
‰
‰
Respiratory
Cardiac
GI (neuronal and muscle)
Developmental Delay
„
„
„
„
„
First, it is not completely clear how delays in
cognition and motor function occur.
Many, if not most, with a mitochondrial disease have
both cognitive and motor delays.
It is likely the energy deficit causing decreased
neuronal axonal sprouting, axonal growth,
decreased/increased pruning, and excess cell
death.
Deficits are more pronounced in those regions that
are most dependent on energy and/or more axonal
inputs and outputs.
Insults can exacerbate problems with cognition.
Patient
„
Case 1:
‰
‰
‰
Patient was 8 years old and developed seizures.
She was eventually diagnosed with a complex III
disorder.
She was placed on Topamax, which controlled
her seizures.
„
Known side effects of Topamax are word finding
problems and slowing of processing speed.
Case 1: Patient drawing at age 7 years.
Case 1: Patient drawing at age 8 years
Case 1.
„
She underwent neuropsychological testing when
she was seizure-free on Topamax.
‰
‰
‰
„
Functional IQ was 85
Verbal IQ was 100; Performance IQ was 65.
She had a greater than 30 point split on actual and
performance verbal and non-verbal testing.
I then switched her seizure medication from
Topamax to Lamictal.
‰
‰
We also added antioxidant treatment with coenzyme Q10,
vitamin E and C, and carnitine.
Case 1
„
After the switch to Lamictal:
‰
‰
‰
„
Functional IQ, actual was 102, Verbal IQ was 118 and
performance IQ was tested at 84.
Verbal split between verbal IQ and performance IQ was 34
points.
Non-verbal performance was abnormal with
„ Difficulties in design memory etc.
Recently, her design for a Christmas card won a
local competition as was selected as one of the
cards used for the last holiday season at our
children’s hospital.
Developmental Delay
„
„
„
„
This case shows that a patient with
mitochondrial disease can be very sensitive
to medications.
She is unusual, as most of the induced deficit
could be reversed by altering her medication.
We have some information that other patients
responded similarly. We don’t know if all
patients will have similar responses.
Cognitive changes are extremely common in
many patients with mitochondrial disease.
Non-Verbal Performance
„
We have performed neuropsychological
testing on 25 children.
‰
‰
Ages ranged from 5 – 20 years.
Electron transport chain defects: N=17
„
‰
‰
Primary Coenzyme Q deficiencies: N=2
mtDNA mutations: N=5
„
‰
Single and multiple complex defects
3700G>A, 3243A>G, mt DNA deletions (KSS)
Nuclear DNA mutations: N=1
„
467A>T homogygote
Non-Verbal Performance
„
The average difference between verbal IQ and
performance IQ (Verbal > Performance):
‰
‰
‰
Mean: -19.
Range: + 2 – 42.
Larges difference seen: All patients had normal MRI scans
of the brain.
„
„
„
‰
Primary coenzyme Q deficiencies -33 and -42 (brothers).
MELAS: - 25.
Kearns-Sayre: - 29 (normal MRI scan at the time testing).
Only a single patient had a performance IQ > verbal IQ.
„
She had a complex III and a heart transplant.
Motor Delay
Motor Delay
„
The back part of the brain is responsible for tone,
coordination (part of which is fine motor skills) and
deep tendon reflexes.
‰
„
The cerebellum is a very high energy demanding
system.
‰
„
Cerebellum
Neuron connections with the motor part of the brain as well
as the deep gray structures (basal ganglia).
Many mitochondrial disease patients have difficulties
with: hypotonia, un-coordination, and fine motor skill.
‰
This part of the brain is also responsible for ataxia (fine
coordination with smooth movement as well as gait).
Fine motor skills
Fine motor skills
„
„
„
There is a technique called functional MRI or
otherwise known as fMRI.
This technique uses the same instrument as the
MRI to locate the source of increased neuronal
activity (which is seen by increased blood flow,
BOLD signal, or as we know it, oxidative
phosphorylation).
Increased blood flow shows neuronal activity.
‰
„
The more activity, the more blood is needed as oxygen
demand increases.
One way of testing fine motor skill is to have the
patient tap their finger during a fMRI scan.
Patient from Case 1. Finger tapping
Finger tapping on fMRI
„
„
What we see here is that the red spots are areas of
increased neuronal activity.
We are beginning to find that patients with
mitochondrial disease have increased areas of
neuronal activity with motor activity.
‰
„
Larger area than seen in non-mitochondrial disease
patients.
You can also see that the motor strip for finger
motor movement and the cerebellum are involved.
‰
Cerebellar activation larger than seen in non-mitochondrial
disease patients.
Treatment
„
„
Currently, we do not know of any medical
treatment for cognitive delays in language or
in motor skills.
However, knowing that most mitochondrial
patients possess a non-verbal learning
disorder, we can modify how a patient is
taught to maximize learning.
‰
„
Auditory learning is easier than reading.
We have a long way to go in this area.
Epilepsy
„
„
„
„
Epilepsy is defined by two or more unprovoked
seizures.
Seizures are transient clinical events that are the
result of abnormal excessive electrical activity within
a population of cerebral neurons.
Clinical events are not always positive events such
as repetitive motor movements or stiffening.
Many seizures are characterized by “negative
phenomena” such as loss of awareness or muscle
tone.
Epilepsy
„
Patients with mitochondrial disease may also have
paroxysmal events or movements which may
confuse the diagnosis.
‰
‰
‰
„
Behavioral “tuning out” or staring.
Stereotypies, such as hand flapping or turning in circles.
Dystonia or abnormal position of an extremity.
All epileptic seizures arise from abnormal cerebral
activity and abnormal electroencephalogram (EEG)
changes.
‰
‰
All patients with mitochondrial disease and suspected
seizures need to have an EEG.
Any new event thought to be seizures, there should be an
EEG performed to try and evaluate the event.
Types of Epilepsy
„
One of the reasons we do the EEG, MRI scan, and
take a very detailed history concerning what the
seizures look like (seizure semiology) is that we
want to figure out if your child has a particular
epilepsy syndrome.
‰
‰
‰
‰
Helps us predict which seizure medications work the best
to control seizures.
Helps to predict long term seizure control.
Helps to indicate if epilepsy surgery is an option.
Helps to differentiate between epileptic seizures and
involuntary movements.
Type of Epilepsy: Epilepsy Syndromes
„
Infantile Spasms
‰
‰
Consists of a specific EEG pattern called
hypsarrhythmia, epileptic spasms, and
developmental regression or stagnation.
Most develop Infantile spasms in early infancy, 4
months to 1 year with the most frequent age of 6
months.
EEG Hypsarrhythmia Pattern
Seizures
„
Epileptic Spasms
‰
‰
‰
‰
Quick jerks that have a 0.5 sec to 1 sec sustained tonic
component.
Often will drop head, extend arms and legs with bending at
the waist (most classic spasm description).
Tend to occur in clusters of 2 – 50 with multiple clusters in
a day.
Natural history: usually begin between 4 months and 1 year
of age.
„
„
Median age is 6 months.
Spasms will usually stop after 3 – 4 years.
Treatment
„
The de facto standard of care:
‰
ACTH is considered first line
„
„
„
„
‰
Efficacy is 60% - 80%
Lots of side effects
Very expensive: $23,000 per vial, average 4 – 6 vial per
treatment.
We have found this works well to stop spasms and alter
the EEG pattern.
Other medications:
„
„
Vigabatrin, Zonisamide, Topamax, Valproic Acid,
Benzodiazepines, Ketogenic Diet
New medication with possibilities: Ganaxolone
Mitochondrial Disease and Infantile
Spasms
„
In our series of patients with electron transport chain
defects:
‰
‰
12/67 (18%) patients had infantile spasms.
ACTH was used in 11 patients
„ 9 responded to ACTH with seizure freedom.
‰
‰
All 9 eventually developed seizures after ACTH was stopped.
2 patients did not respond to ACTH.
‰
1 patient became and stayed seizure free on the
ketogenic diet.
‰
11/12 eventually developed other seizure types and
continued to have seizures that were unresponsive to a
variety of seizure medications, including the ketogenic diet.
SE-MISF Syndrome
„
The most common epilepsy syndrome in patients
with electron transport chain defects is SE-MISF
syndrome.
‰
‰
Severe Epilepsy with Mulitfocal Independent Spike Foci
(SE-MISF).
Initially described by Noriega-Sanchez and Markand
(1976).
„
„
„
„
Electroclinical syndrome-meaning that it is base on the EEG
pattern and clinical seizures.
Looked at 108 patients
Intellectual and neurological deficits.
Many etiologies: CNS infections, Trauma, Hypoxia,
Malformations of cortical development, gene defects (SCN1A).
SE-MISF Syndrome
„
Literature suggests that highest incidence is
between 4 – 7 years.
‰
„
Multiple seizure types:
‰
„
„
But seen in age range from 2 months to 47 years.
Spasms, atypical absence, myoclonic jerks, and
short tonic seizures.
Most patients are intractable to seizure
medications.
Majority of patients are developmentally
delayed or mentally retarded.
SE-MISF Syndrome
„
Mitochondrial Disease:
‰
42/67 patients with electron transport chain
defects and seizures had this syndrome.
„
‰
Single or multiple electron transport chain
complexes were dysfunctional.
„
‰
Includes 11/12 patients with Infantile Spasms that later
developed this syndrome.
Most common complex abnormality was complex III.
Median age of seizure presentation was 3 years.
SE-MISF Syndrome: EEG
SE-MISF Syndrome:EEG
SE-MISF Syndrome: Seizures
„
Seizure types:
‰
‰
‰
‰
‰
Atypical Absence: Staring with unresponsiveness.
Epileptic Spasms: As with Infantile Spasms.
Myoclonic Seizures: Quick jerks of the whole
body, one side of the body, or one limb.
Short Tonic Seizures: Stiffening for a short time,
usually 2 – 20 seconds. May show some cyanosis
around the lips.
Non-specific motor seizures: Abnormal rhythmic
or stiffening of a limb or a part of a limb.
SE-MISF Syndrome: Treatment
„
Treatment is unsatisfactory:
‰
Most patients are on 3 or more seizure medications.
„
‰
Several are on the ketogenic diet with some efficacy but no
patient in our series is seizure free.
„
‰
1/8 patients have become seizure free on the diet.
5 Patients (<12 years) had the VNS placed and no patients
had a benefit. (Arthur et al., 2007)
„
„
‰
Medication have helped reduce seizure frequency, but not
seizure freedom.
All 5 had multiple seizure types without benefit in any of the
seizure types.
We have a total of 10 patients, none of them have had a
response from VNS placement.
Hopeful of the medication Ganaxolone coming to market.
PE-MISF Syndrome
„
„
„
„
Milder epilepsy with mainly focal or partial
seizures (Partial Epilepsy with Multifocal
Independent Spike Foci: PE-MISF).
The EEG is similar to SE-MISF.
However, these patients has seizures that
are easier to control.
Seizures are usually atypical absence or nonspecific motor seizures.
PE-MISF Syndrome: Mitochondrial
Disease
„
In our series:
‰
‰
8/67 patients with PE-MISF.
Most common patient has a complex I defect.
„
‰
5/8 have a complex I defect.
Treatment is more optimistic with many seizure
free.
„
6 are seizure free on one or two medications.
‰
„
Lamictal, Lamictal + Keppra, Zonisamide, Clobazam.
2 patient have infrequent seizures, < 1 month.
‰
Lamictal, Keppra, Valproic acid (use with caution).
Generalized Epilepsy
„
„
The EEG shows generalized discharges.
Generalized Epilepsy Syndromes
‰
„
Childhood absence, Juvenile Myoclonic Epilepsy,
Generalized tonic clonic upon awaking, etc.
Seizure types:
‰
Typical Absence, atypical absence, generalized
tonic clonic, tonic, clonic, and myoclonic.
Generalized Epilepsy: EEG
Generalized Epilepsy: Mitochondrial
Disease
„
In our series of patients with electron
transport chain defects):
‰
‰
‰
‰
12/67 had generalized discharges.
Most common was complex I defect (4/12).
Seizures: Atypical absence, myoclonic, tonic, and
epileptic spasms.
Seizure control is problematic as with SE-MISF.
„
„
9/12 continue to have seizures on multiple seizure
medications.
3 patients in control are on Valproic acid, Zonisamide,
Lamictal, Clobazam.
Generalized Epilepsy: Mitochondrial
Disease
„
„
Classic mitochondrial syndrome due to
mitochondrial DNA mutation at 8344 (80%).
Myoclonus epilepsy with ragged-red fibers
(MERRF).
‰
‰
‰
‰
Normal development with seizures developing
from 3 years to adulthood.
Myoclonic seizures and myoclonia.
Intractable seizures with progressive cognitive
decline.
Muscle biopsy shows ragged-red fibers.
Epilepsy and Mitochondrial Disease
„
Thoughts and Conclusions
‰
Approximately 50% of children with electron
transport chain defects have seizures.
„
‰
‰
Infants with electron transport chain defects can
present with Infantile spasms.
Most children with electron transport chain defects
and seizures:
„
‰
Why only 50%?
SE-MISF syndrome is the most common in our series.
Unfortunately, treatment remains unsatisfactory.
Epilepsy Mimics and Involuntary
Movements
„
Few things in neurology have repetitive
movements.
‰
‰
Seizures
Involuntary movements
„
‰
‰
‰
Dystonia, Athetosis, Chorea
Tics
Stereotypies
Tremor
Epilepsy Mimics and Involuntary
Movements
„
To investigate:
‰
‰
‰
‰
„
Home video the movement
Video-EEG
EEG
MRI
To avoid:
‰
Seizure medications when the repetitive
movements are not seizures.
„
Exceptions may be tics (Topamax), Dystonia or other
basal ganglia induced movements (Carbamazepine or
Keppra)
Valproic Acid
„
„
„
„
Very important seizure medication, as it helps to
control both generalized and partial seizures.
However, its use in mitochondrial disease should be
monitored with extreme caution.
Valproic acid has been shown to induce/accelerate
liver failure in patients with Alpers (POLG
mutations).
Valproic acid has been shown to cause reversible
brain atrophy and encephalopathy in small numbers
of patients with mtDNA mutations.
Sleep
„
„
Sleep is absolutely required but we really
don’t know why.
When your son/daughter don’t sleep, you
don’t sleep either.
‰
„
Is this true? Yep at least at my house.
Sleep problems
‰
‰
‰
Getting to sleep.
Staying asleep.
Poor oxygenation during sleep.
Sleep
„
„
„
Sleep problems associated with ADHD,
increased seizures, headache, personality
changes, obesity and behavioral problems.
There are sleep centers within the brain
(brainstem) that are often affected as part of
the pathology of the mitochondrial disease.
Sleep studies can be helpful to diagnosis
possible sleep disorders and validate
treatment efficacy.
Sleep Treatments
„
Difficulty getting to sleep:
‰
Sleep hygiene (in all patients).
„
‰
Strict sleep schedule, no lights in room, etc.
Medications: My preference in order„
„
„
„
„
„
Melatonin
Rozerem
Clonidine
Risperidal
Trazadone
(benzodiazepines, i.e. ambien are only short term
solution and I have not found they work well).
Sleep Treatments
„
Difficulty in staying asleep: medications in
order of preference‰
‰
‰
‰
Time released melatonin
Rozerem
Sending to grandparents house.
There isn’t much out there for staying asleep.
„
However, there are some medications in clinical trials
that may help answer this question.
Sleep Treatments
„
Restless leg syndrome
‰
‰
‰
Gabapentin (neurontin)
Tegretol
Requip
Sleep Treatments
„
Some sleep disorders are actually seizures.
‰
‰
Video-EEG for diagnosis is often necessary.
Differential: Sleep paroxysmal events Vs seizures
„
„
„
„
‰
Head banging
Sleep walking
Night terrors
REM behaviors
Suggestion that night time behaviors are seizures:
„
„
Multiple events a night
Events occur at various times during sleep
Autonomic Failure and GI Dysmotility
„
Symptoms:
‰
‰
‰
‰
‰
‰
Failure to thrive
Severe reflux
Vomiting (cyclic and/or non-cyclic)
Severe constipation
Severe diarrhea
Pseudo-obstruction
Autonomic Failure and GI Dysmotility
„
Treatments (individualize)
‰ Medications for reflux
‰ Mitochondrial vitamins
‰ Formula changes
„
‰
Alteration of choices of foods
„
‰
Formulas (Pedisure and others) to add to regular diet.
Alteration of routes of intake
„
„
„
‰
Elemental formula
NG
G-tube
Combinations (G-tube feeding at night)
Timing of feedings
„
„
„
Increased meals
Night time feeds
Continuous feeding
Autonomic Failure and GI Dysmotility
„
Increasing calories
‰
‰
‰
May or may not help.
Vary formulas with higher number of calories per
once.
Adding MCT oil
„
„
„
1 tbs = 50 kcals
TPN (feeding via IV line)
IVIg for pseudo-obstruction
Headache: Migraine
„
Migraine
‰
‰
„
Migraine without aura
Migraine with aura
Treatment
‰
Triggers should be avoided, headache diary helps.
„
‰
Always think about sleep apnea or night time hypoventilation.
If infrequent
„
„
Periactin if young (< 6yrs)
Ibuprofen
‰
„
„
Ibuprofen + Benadryl
Neurontin
Tryptan (> 12 years)
Headache: Migraine
„
Migraine
‰
If frequent
„
„
‰
Riboflavin 400 – 600 mg before bed.
CoQ10 25 – 100 mg
If very frequent
„
„
Youngster: Periactin (up to 4 mg qid)
Amitroptyline (up to 2/mg/kg per day)
‰
„
„
Do ECG to check for long QTc
Neurontin
I stay away from beta-blockers and calcium channel
blockers.
Headache: Migraine
„
Migraine Variants
‰
‰
‰
Confusional migraine
Hemiparesis or aphasic (can’t talk)
Cyclic vomiting
„
Must differentiate from fatty oxidation problem, electron
transport chain defect, cholesterol metabolic defect,
mitochondrial DNA mutation, nuclear mitochondrial gene
defect (i.e. POLG mutations).
Transient Encephalopathy
„
Migraine variant or distinct entity?
‰
Patient who every fall has a 1 – 2 month period
where she will become encephalopathic.
„
‰
Complex I defect
Patient who every 3 – 4 months becomes
encephalopathic.
„
„
For 1 – 2 weeks becomes encephalopathic
Currently unclear etiology, working him up for possible
mitochondrial disorder.
Stroke and Stroke-like Events
„
Fine line between complicated migraine,
stroke and seizure, especially in MELAS.
‰
New onset seizure
„
„
‰
New onset of migraine
„
‰
EEG
If focal then MRI
Consider MRI
New onset neurological abnormality
„
MRI
Stroke and Stroke-like Events
„
Often if the MRI shows new onset stroke,
hospitalization is necessary.
Stroke and Stroke-like Events
„
Treatment:
‰
Not from a vascular source (i.e. artery).
„
‰
Treatments for usual stroke etiologies not appropriate for most
mitochondrial patients, such as tPA.
For most mitochondrial patients:
„
„
„
„
IV hydration
IV carnitine (maybe)
Supportive care
Many patients present with seizures or headache
‰
‰
„
EEG
MRI
Some case reports suggest that L-arginine may be helpful to
prevent further strokes in MELAS.
Psychiatric Problems
„
„
„
Accurate diagnosis is the initial best step
Diagnosis is confirmed then usual psychiatric
treatment is likely best.
However, let me present a case where
thinking “outside the box” was helpful.
Case
„
„
„
„
Patient is currently a 16-year old boy with history of
early onset seizures, episodic hemiplegia, global
developmental delay and long standing behavioral
problems of aggression, acting out, and austic like
behavior.
Recently admitted to the pediatric psychiatric ward
for increasing agitation and behavioral outburst.
Consulted as question of seizures causing
behavioral outburst.
EEG was performed.
‰
‰
No events recorded,
EEG was abnormal showing spikes but not seizures.
Case
„
„
„
We decided to recheck his endocrine system.
His TSH was low as well as T4.
‰ Currently further investigating.
His FSH is elevated as well as testosterone levels.
‰ Talking with the psychiatrists, we think that his aggressive
behavior as well as acting out (hitting, biting, etc) may be related
to his elevated testosterone level.
‰ It is not obvious to us why his pituitary axis has changed.
‰ Mitochondrial dysfunction?
‰ His mitochondrial disease is not clear, abnormal mitochondrial
numbers and morphology on muscle biopsy. His ETC was not
revealing. He has some abnormal biochemistries suggestive of a
mitochondrial disease.
‰ Just began to give him testosterone reducing medications.
Conclusions
„
„
„
Many different neurological manifestations of
mitochondrial disease.
Standard diagnostic testing encouraged early in the
disease course and may need to be repeated often.
Many conditions have no standard treatments.
‰
‰
„
„
Uncertainty for parents, patients as well as physicians.
Begin with usual treatment for the symptom.
Work with your local mitochondrial expert as well as
your family/pediatrician/internist.
As a group, we need to pool our experiences to
begin to develop treatment strategies for varying
types of mitochondrial disease.